Clinical Impact of HPV Self-Sampling and Molecular Biomarkers on Cervical Cancer Screening and Triage: “The Times They Are A-Changin’”—A Comprehensive Review and Future Perspectives

Human papillomavirus (HPV) infection is a necessary but insufficient cause of cervical cancer (CC) and reflects a long-standing host–virus equilibrium shaped by immune control, viral persistence, and latency. The transition from cytology-based screening to primary high-risk HPV testing has substantially improved early detection of cervical precancerous lesions but has also introduced new clinical challenges related to fluctuating test results, overdiagnosis, overtreatment, and patient anxiety, whose magnitude may vary across countries depending on screening organization and access to prevention services. This narrative review provides a clinically oriented overview of HPV-based CC screening in the context of evolving knowledge on HPV natural history, persistence, and immune interaction, and discusses the implications for the interpretation of test results and risk stratification. New emerging screening and triage approaches, including molecular biomarkers, exosome-based biomarkers, and artificial-intelligence-supported risk assessment, are reshaping CC prevention strategies by enabling more precise identification of women at risk for clinically significant disease. These tools may be particularly relevant in self-sampling-based screening pathways, where molecular triage strategies can reduce the need for additional clinician-collected samples and improve management of HPV-positive women. At the same time, improved understanding of viral latency and host-related determinants of progression supports a shift from binary test interpretation toward longitudinal and individualized risk assessment. Integrating biological insight with technological innovation may facilitate personalized screening strategies that maintain high sensitivity while reducing unnecessary interventions. An evolutionary-informed and risk-adapted approach to HPV-related disease management is essential to optimize prevention outcomes and preserve the benefits of population-based screening programs.